This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Project 1: Endothelial progenitor cell (EPC) mobilization defects in diabetes Diabetes is associated with a wide spectrum of cardiovascular diseases that are best characterized by a dysfunctional endothelium an impaired capacity for its repair. The central hypothesis of this project is that these vascular abnormalities result from a loss of circulating EPCs due to defects in their mobilization from the bone marrow. To test this hypothesis we will: 1. Define diabetes-induced changes in EPC populations: Using murine models of Type I and/or Type II diabetes, we will quantify levels of antigenically-defined EPC populations in peripheral blood, spleen and bone marrow;determine if these effects are specific to early/late or non-monocytic/monocytic EPCs;and determine when these effects become prominent during disease progression. To establish specificity, we will determine whether the effects of diabetes are unique to EPCs, or whether mesenchymal (MSC) and hematopoietic (HSC) stem cells are also affected;and 2. Delineate the mechanisms by which diabetes limits EPC mobilization: To assess the involvement of integrin-mediated adhesion, we will examine the properties of alpha4 beta1 and EPC levels in mice expressing alpha4 variants. To determine whether MMPs are deficient, we will examine their levels in the bone marrow of diabetic mice and in the media of cultured cells. To establish a role for the polyol pathway, we will characterize EPCs, diacylglycerols (DAGs), reactive oxygen species (ROS) and PKC activity levels in diabetic wild type and aldose reductase (AR) knockout mice;and 3. Evaluate the reparative efficacy of EPC mobilizing strategies: Based upon Aim 2 studies, we will examine the efficacy of interventions in promoting neo-vascularization and wound repair in diabetes.